Theory of cancer evolution

Question 1

ulceration of skin from tumour seen in …

Answer 1

melanoma

Question 2

key features of malignant tumours (4)

Answer 2

1. Multiple mutations
2. Disorganised growth
3. Loss of function
4. Intensive angiogenesis

Question 3

H1 of evolution in cancer:

Answer 3

‘cells in malignant tumours evolve by natural selection’

Question 4

immune cells cant see tumours due to …

Answer 4

escaping immunosurveillance

Question 5

multi-step tumorigenesis, 3 examples;

Answer 5

(1) somatic mutation (occurs in NORMAL tissue)
(2) PRE-CANCER/malignancy (genetic diversity leading to malignancy
(3) somatic evolution in CANCER itself

Question 6

Why humans have more cancer than other species?

Answer 6

1. long reproductive lifespan
2. mis-matched to risk factors (high-calorie/fat, pollution etc.) - not evolved for this lifestyle
3. highly adaptive placenta, made by stem cells, which are pre-adapted to metastasis

Question 7

high or low prevalence of covert (sub-clinical) cancer?

Answer 7

HIGH
e.g. cancer found in autopsies (almost 50% of males dies with prostate cancer)
e.g. covert malignant cancers
e.g. pre-malignant carcinomas in-situ found in autopsies

Question 8

The cancer lottery dependant on … (3)

Answer 8

• if mutations occur in stem cells (already have ability to proliferate and divide) - so chance of cancer is increased
• modulators of risk
  e.g. cancer susceptibility loci (pre-disposed to cancer - inherited), diet, immune system
• chance

Question 9

Somatic mutation theory (SMT) of cancer
(two-hit hypothesis)

Answer 9

genetic change in single cell
vvv
passed onto progeny
vvv
= clone of cells
vvv
further mutations acquired
vvv
sub-clone emerges - that can grow + metastasise = death of host

Question 10

the two-hit hypothesis shows …

Answer 10

somatic mutation alone is not a driving force of cancer

Question 11

micro-evolution e.g.

Answer 11

antibiotic resistance (occurs in population)

Question 12

macro-evolution e.g.

Answer 12

speciation (occurs at/above level of the species)

Question 13

gradualism

Answer 13

gradual changes in phenotype of (cancer) cell

Question 14

punctuated equilibrium

Answer 14

immediate/massive change that leads speciation

Question 15

somatic evolution =

Answer 15

accumulation of mutations in somatic cells over a lifetime
(NOT germ & stem cells)
these mutations increase with age/risk exposures

Question 16

varient allele frequency

Answer 16

how many cells/clones have a certain mutation

Question 17

clone

Answer 17

set of cells that descend from a common ancestor cell (distinguished by distinctive cell lesion inherited from the ancestor cell)

Question 18

Neoplastic progression

Answer 18

evolutionary process, normal tissue changes into malignant tissue

Question 19

shannon index define:

Answer 19

estimates genetic diversity (describes variation at multiple levels of genetic organisation (e.g. SNPs t ecosystems)

Question 20

divergence define:

Answer 20

measures amount of diversity in a clone
/
assesses the genetic differences that have accumulated between clones

Question 21

driver mutation =

Answer 21

gives selective advantage to a clone in microenvironment
(tend to cause clonal expansions)

Question 22

passenger mutation =

Answer 22

has no effect on fitness of clone
can be a hitchhiker - occurs in the same genome with a driver mutation - associated with clonal expansion

Question 23

trisomy

Answer 23

= 3 copies of a Chr
(hallmark of B cell malignancies)

Question 24

mechanisms that create diversity (4)

Answer 24

1. numerical chromosomal instability
2. structural chromosomal instability
3. somatic mutagenesis
4. epigenetic heterogeneity

Question 25

structural chromosomal instability, macroevolution; (chromoplexy and chromothripsis)

Answer 25

chromoplexy: in one division, disordered rearrangement across genome
&
chromothripsis: complex chromosomal rearrangement (many clusters of rearrangements simultaneously + localised)

Question 26

intratumour heterogeneity

Answer 26

1. linear evolution
2. branching evolution
3. neutral evolution
4. punctuated evolution

Question 27

ITH: Branching evolution (normally what’s seen in tumour evolution)

Answer 27

different cells of clones gather different mutations and evolve
(multiple clonal lineages)

Question 28

ITH: Neutral evolution

Answer 28

lots of mutations gathered
not going under selection yet

Question 29

ITH: punctuated evolution

Answer 29

chromoplexy/thripsis causes jump from tumour initiation to new clone

Question 30

problems with treating branching evolution cancers …

Answer 30

wrong therapy given at metastasis stage (when treatment is normally given)
can select for a really aggressive clone

Question 31

cancer as a complex system … whats important in the selective process … (2)

Answer 31

• biological features (eg. (architectural constraints) basement membranes, restricted niches)
  &
• regulatory systems (eg. hormones + GFs, immune system)